Aberrant hyperactivation of KRAS plays a prominent role in tumor initiation and progression in a broad spectrum of human cancers. KRAS mutations comprise 86% of all RAS mutations and are associated with the highest frequency, roughly 22%, of all human malignancies (1). The incidence of KRAS mutations is especially high in pancreatic and colorectal malignancies, where it occurs at a frequency of greater than 90 and greater than 40%, respectively. Pancreatic and colorectal cancers are among the most lethal of all cancers and are the fourth and third leading cause of cancer deaths in the US (2). Approximately 80% of all pancreatic cancer cases present with locally advanced or metastatic disease, which precludes surgical intervention. Currently, there are no curative options for the treatment of KRAS-activated cancers. Treatment options for KRAS mutant patients with metastatic colorectal cancer who have failed first-line chemotherapy with a fluoropyrimidine and oxaliplatin are also limited.
Efforts to develop drugs that directly target mutant KRAS remain challenging because specificity issues are problematic. Consequently, efforts at pharmacologic intervention of KRAS signaling have focused intensively in recent years on downstream targets in the two central RAS effector pathways, RAF/MEK/ERK and PI3K/AKT/mTOR (3, 4). RAF and MEK have spawned a number of drug discovery programs that have resulted in attractive clinical candidates (5-7). Clinical activity of BRAF inhibitors likely will be restricted to patients with BRAF mutated tumors because the absence of a BRAF mutation is associated with induction, rather than inhibition, of MAPK signaling in response to this targeted approach (8-10). In contrast, MEK inhibitors have been shown to exert antiproliferative effects in roughly half of the KRAS mutant tumors tested (11). It is encouraging that the MEK inhibitor CI-1040, as well as trametinib, have both elicited objective responses in Phase 1 testing (12, 13). MEK inhibition therefore is a viable approach for the treatment of KRAS activated cancers, but in a monotherapy setting, MEK inhibition is unlikely to produce the degree of activity needed to significantly impact outcome in this refractory patient population.
One strategy to improve upon MEK inhibitor single agent activity is the additional targeting of PI3K signaling. This combination strategy is based on in vitro and in vivo evidence suggesting that KRAS mutant tumors require dual inhibition of both the MAPK and PI3K pathways to achieve maximal inhibition of tumor growth (11, 14-16). Release of negative feedback loops has been shown to lead to activation of the alternate pathway when either one is inhibited (16, 17). Activation of the PI3K pathway, commonly due to PI3KCA mutations or PTEN loss, represents a major resistance mechanism to MEK inhibitor therapy in KRAS mutant cancers. Combined inhibition of both pathways leads to a significant increase in apoptosis and tumor shrinkage (18).
Because the RAS/RAF/MEK/ERK signal transduction pathway is activated in a significant percentage of the most aggressive and deadly forms of human cancers, several small molecule inhibitors targeting this pathway have either been FDA approved or are in active clinical development. Unfortunately, despite the clinical efficacy of a commercially-available BRAF inhibitor, i.e., PLX4032 or Vemurafenib, in treating tumors bearing both BRAF and KRAS activating mutations, the drug is ineffective against tumors with native BRAF due to paradoxical induction of ERK signaling.
MEK and PI3K inhibitors therefore are known in the art. For example, Iikura et al. U.S. Pat. No. 7,897,792 discloses a class of coumarin-based MEK inhibitors. PI3K inhibitors are disclosed, for example, in U.S. Patent Nos. 2010/0249099; 2011/0009405; and 2011/0053907. The combined use of PI3K and MEK inhibitors to treat lung cancer is disclosed, for example, in Engelman et al., Nature Medicine, Vol. 14, Number 14, pages 1351-56 (2008).
However, a need still exists in the art for compounds and methods to treat cancers and other diseases and conditions by inhibition of MEK and PI3K. Despite the discovery of small molecular inhibitors MEK and PI3K, the design of potent, inhibitors of MEK and PI3K remains a significant challenge in modern drug discovery. Accordingly, a need still exists in the art for MEK and PI3K inhibitors having physical and pharmacological properties that permit use of the inhibitors in therapeutic applications. The present invention provides bifunctional compounds designed to bind to MEK and PI3K, and to inhibit MEK and PI3K activity.